YTHDC1 mediates nuclear export of N6-methyladenosine methylated mRNAs

By I. A. Roundtree, Guan-Zheng Luo, Zijie Zhang, Xiao Wang, Tao Zhou, Y. Cui, J. Sha, Xingxu Huang, Laura Guerrero, Phil Xie and 3 more. eLife, 2017

1,035 citations recorded by the source corpus.

N6-methyladenosine (m6A) is the most abundant internal modification of eukaryotic messenger RNA (mRNA) and plays critical roles in RNA biology. The function of this modification is mediated by m6A-selective ‘reader’ proteins of the YTH family, which incorporate m6A-modified mRNAs into pathways of RNA metabolism. Here, we show that the m6A-binding protein YTHDC1 mediates export of methylated mRNA from the nucleus to the cytoplasm in HeLa cells. Knockdown of YTHDC1 results in an extended residence time for nuclear m6A-containing mRNA, with an accumulation of transcripts in the nucleus and accompanying depletion within the cytoplasm. YTHDC1 interacts with the splicing factor and nuclear export adaptor protein SRSF3, and facilitates RNA binding to both SRSF3 and NXF1. This role for YTHDC1 expands the potential utility of chemical modification of mRNA, and supports an emerging paradigm of m6A as a distinct biochemical entity for selective processing and metabolism of mammalian mRNAs.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/302be88c84e658e1b87655eb8d9b9b4b865676c1

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

1. Chuan He
2. P. He
3. Hailing Shi
4. E. Lengyel
5. Jianzhao Liu

In Molecular Biology

1. Chuan He
2. P. He
3. Hailing Shi
4. Syuzo Kaneko
5. Masaaki Komatsu
6. Ken Asada
7. Ken Takasawa
8. Jiangbo W

Citations in the corpus

• LNCcation: lncRNA localization and function (2021, result): “…al., 2016; Rossi et al., 2019; Stein et al., 2018; van Heesch et al., 2019); however, that lncRNA association with polysomal fractions is indicative of active translation (Ingolia et al., 2011; Ruiz-Orera et al., 2014) is not supported by other studies (Bánfai et al., 2012; Guttman et al., 2013).”
• Critical Roles of N6-Methyladenosine (m6A) in Cancer and Virus Infection (2020, background): “Consistent with this role, YTHDC1 enhances nuclear export of m6A-modified mRNAs via the nuclear export pathway with SRSF3, the canonical mRNA export receptor, and nuclear transcription factor X-box binding 1 (NXF1), whereas YTHDC1 knockdown leads to deficient export of target mRNAs [68].”
• Dynamic transcriptomic m6A decoration: writers, erasers, readers and functions in RNA metabolism (2018, background): “They do not bind to m6A directly, but instead, m6A serves as a structural switch to alter the RNA structure, which renders transcripts more accessible for binding by HNRNPC and HNRNPG. Cytoplasmic m6A readers After being processed from precursor transcripts, mature mRNAs containing m6A are further r”
• m6A mRNA methylation regulates AKT activity to promote the proliferation and tumorigenicity of endometrial cancer (2018, positive): “…mediate the reversal of this methylation 3,9 . m 6 A methylated transcripts are recognized by reader proteins that regulate pre-mRNA processing 10–14 , translation 15–19 , and degradation 10,19,20 . m 6 A-dependent mRNA regulation is essential in mammals 21 , and defects in m 6 A methylation…”
• m6A RNA methylation: from mechanisms to therapeutic potential (2021, positive): “…exerts a positive, neutral, or negative effect on infection, depending on the virus (Williams et al , 2019). m 6 A on host RNA appears to suppress the anti-viral interferon response, as METTL3 or METTL14 depletion leads to an increase in IFN b expression (Rubio et al , 2018; Winkler et al , 2019).”
• FMRP Modulates Neural Differentiation through m6A-Dependent mRNA Nuclear Export (2019, neutral): “…(m 6 A) is emerging as a critical mechanism regulating different aspects of RNA metabolism and function, including stability (Du et al., 2016; Ke et al., 2017; Wang et al., 2014), localization (Roundtree et al., 2017), and translation (Lin et al., 2016; Meyer et al., 2015; Wang et al., 2015).”
• The potential role of RNA N6-methyladenosine in Cancer progression (2020, background): “promoting the export of m6A-methylated mRNAs from the nucleus [33, 34].”
• Where, when and how: context-dependent functions of RNA methylation writers, readers, and erasers (2019, background): “Building on the understanding of its widespread prevalence on mRNA, recent work has uncovered that m6A plays an important role in gene expression regulation (Roundtree et al., 2017a), animal development (Frye et al., 2018), and human diseases (Hsu et al., 2017a).”
• Functions of N6-methyladenosine and its role in cancer (2019, background): “YTHDC1 contributes to RNA splicing and export [27, 28]”